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Tranilast prevents the progression of experimental diabetic nephropathy through suppression of enhanced extracellular
Hiroshi Akahori1, Tsuguhito Ota, Muneyoshi Torita
1Department of Diabetes and Digestive Disease, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa, Japan 920-8641.
Abstract:
The present study was performed to investigate the effects of the antiallergic drug tranilast on the development of diabetic nephropathy in streptozotocin (50 mg/kg)-induced diabetic spontaneously hypertensive rats (SHR). Diabetic SHR were given standard chow or chow containing tranilast at a dose of 1400 mg/kg for 24 weeks. The effects of tranilast on urinary albumin excretion, mesangial expansion, expression of transforming growth factor-beta (TGF-beta) and type I collagen mRNAs, number of anionic sites on the glomerular basement membrane (GBM), and urinary TGF-beta and 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion were assessed. Tranilast did not affect the blood glucose concentration or blood pressure in diabetic SHR. Urinary albumin excretion rate and creatinine clearance were markedly increased in diabetic SHR. Tranilast treatment decreased albuminuria and hyperfiltration. Tranilast inhibited the diabetes-induced expansion of mesangial and tuft areas, as well as the increase in urinary TGF-beta and 8-OHdG excretion, loss of anionic sites of GBM, and overexpression of TGF-beta as determined immunohistochemically. The levels of TGF-beta and type I collagen mRNA expression were increased in the renal cortex in untreated diabetic SHR at 24 weeks, as determined by real-time quantitative polymerase chain reaction. Tranilast treatment inhibited the up-regulation of TGF-beta and type I collagen mRNA expression by 65 and 36%, respectively, in diabetic SHR. In conclusion, tranilast decreased albuminuria by suppressing glomerular hyperfiltration, mesangial expansion, and loss of the charge barrier via regulation of extracellular matrix gene expression and oxidative stress. Tranilast may be clinically useful in the treatment of diabetic nephropathy.
Insights
The antiallergic drug tranilast effectively reduced albuminuria and kidney damage in diabetic rats. It suppressed glomerular hyperfiltration and mesangial expansion, suggesting potential for treating diabetic nephropathy.
Area of Science:
- Nephrology
- Pharmacology
- Diabetology
Background:
- Diabetic nephropathy is a major complication of diabetes, leading to kidney damage.
- Early markers include albuminuria and hyperfiltration.
- Transforming growth factor-beta (TGF-beta) and oxidative stress play key roles in its development.
Purpose of the Study:
- To investigate the therapeutic effects of tranilast on diabetic nephropathy.
- To assess tranilast's impact on kidney function and histological changes.
- To evaluate tranilast's influence on specific molecular markers like TGF-beta and oxidative stress.
Main Methods:
- Streptozotocin-induced diabetic spontaneously hypertensive rats (SHR) were treated with tranilast (1400 mg/kg) or standard chow for 24 weeks.
- Evaluated urinary albumin excretion, creatinine clearance, mesangial expansion, glomerular basement membrane (GBM) anionic sites.
- Assessed expression of TGF-beta and type I collagen mRNA, and urinary TGF-beta and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels.
Main Results:
- Tranilast significantly reduced albuminuria and normalized hyperfiltration without affecting blood glucose or pressure.
- Tranilast inhibited mesangial expansion, preserved GBM anionic sites, and decreased urinary TGF-beta and 8-OHdG excretion.
- Tranilast suppressed the upregulation of TGF-beta and type I collagen mRNA expression by 65% and 36%, respectively.
Conclusions:
- Tranilast ameliorates diabetic nephropathy by reducing albuminuria, hyperfiltration, mesangial expansion, and oxidative stress.
- The drug modulates extracellular matrix gene expression and preserves glomerular structure.
- Tranilast shows promise as a clinical treatment for diabetic nephropathy.
